Phenoxycarboxylic acids

ABSTRACT

Phenoxycarboxylic acids of the formula    &lt;IMAGE&gt; I  wherein R, R1, R2, R3, R4 R5, Z and n are as hereinafter set forth, are as described. The compounds of formula I are antagonists of slow reacting substance of anaphylaxis (SRS-A), which renders them useful as agents for the treatment of allergic conditions.

RELATED APPLICATIONS

This application is a division of Ser. No. 460,719, filed Jan. 24, 1983now U.S. Pat. No. 4,507,498, which in turn is a continuation-in-part ofapplication Ser. No. 366,896, filed Apr. 9, 1982 now abandoned.

BRIEF SUMMARY OF THE INVENTION

The invention relates to compounds of the formula ##STR2## wherein R ishydrogen or lower alkyl, R₁ is hydrogen or lower alkyl, R₂ is loweralkanoyl, R₃ is hydrogen or methyl, R₄ is hydrogen or lower alkyl, R₅ ishydrogen, halogen, lower alkyl or lower alkanoyl, Z is lower alkylene,2-hydroxypropylene or --(CH₂)_(s) [O(CH₂)_(s) --_(t), wherein s is theinteger 2, 3 or 4, t is the integer 1, 2 or 3, and n is an integer from1 to 7, or, when R₄ is hydrogen,

salts thereof with pharmaceutically acceptable bases. The compounds offormula I are useful as agents for the treatment of allergic conditions.

In another aspect, the invention relates to intermediates of theformulas ##STR3## wherein R₁, R₂, R₃, R₄ ', Z"', A and n are as hereindescribed.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "lower alkyl" denotes a straight or branchedchain saturated hydrocarbon containing 1 to 7 carbon atoms, for example,methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl,heptyl and the like. The term "lower alkylene" denotes a hydrocarbonradical of 2 to 5 carbon atoms, preferably of 3 to 5 carbon atoms, suchas ethylene, propylene, butylene and pentylene. The term "loweralkanoyl" denotes an alkanoyl group derived from an aliphatic carboxylicacid of 1 to 7 carbon atoms, for example, formyl, acetyl, propionyl,butyryl and the like. The term "halogen" denotes all the halogens, thatis, bromine, chlorine, fluorine and iodine.

The invention relates to compounds of the formula ##STR4## wherein R ishydrogen or lower alkyl, R₁ is hydrogen or lower alkyl, R₂ is loweralkanoyl, R₃ is hydrogen or methyl, R₄ is hydrogen or lower alkyl, R₅ ishydrogen, halogen, lower alkyl or lower alkanoyl, Z is lower alkylene,2-hydroxypropylene or --(CH₂)_(s) [O(CH₂)_(s) ]_(t) wherein s is theinteger 2, 3 or 4, t is the integer 1, 2 or 3, and n is an integer from1 to 7,

and, when R₄ is hydrogen, salts thereof with pharmaceutically acceptablebases, which can be prepared as hereinafter described.

An interesting group of compounds of the invention are compounds of theformula ##STR5## wherein R is hydrogen or lower alkyl, R₁ is hydrogen orlower alkyl, R₂ is lower alkanoyl, R₃ is hydrogen or methyl, R₄ ishydrogen or lower alkyl, R₅ is hydrogen, halogen, lower alkyl or loweralkanoyl, Z' is lower alkylene or 2-hydroxypropylene, and n is aninteger from 1 to 7, or, when R₄ is hydrogen,

a salt thereof with a pharmaceutically acceptable base.

Another interesting group of compounds of the invention are compounds ofthe formula ##STR6## wherein R is hydrogen or lower alkyl, R₁ ishydrogen or lower alkyl, R₂ is lower alkanoyl, R₃ is hydrogen or methyl,R₄ is hydrogen or lower alkyl, R₅ is hydrogen, halogen, lower alkyl orlower alkanoyl, Z" is --(CH₂)_(s) --[--O(CH₂)_(s) --]_(t) --, wherein sis the integer 2, 3 or 4, t is the integer 1, 2 or 3, and n is aninteger from 1 to 7, or, when R₄ is hydrogen,

a salt thereof with a pharmaceutically acceptable base.

Preferred compounds of formula Ia are those wherein R₂ is in the4-position, and R₄ is hydrogen. Of these, the more preferred compoundsare those wherein R₃ and R₅ are hydrogen, Z' is propylene or pentylene,R and R₁ are lower alkyl, and n is 1 or 3. Still more preferredcompounds of formula Ia are those wherein R₃ and R₅ are hydrogen, Z' ispentylene, R and R₁ are propyl, R₂ is acetyl in the 4-position, R₄ ishydrogen and n is 1 or 3.

Preferred compounds of formula Ib are those wherein R₂ is in the4-position, and R₄ is hydrogen. Of these, the more preferred compoundsare those wherein R and R₁ are lower alkyl, R₃ and R₅ are hydrogen, andn is 1 or 3. Still more preferred compounds of formula Ib are thosewherein R₃ and R₅ are hydrogen, R and R₁ are propyl, R₂ is acetyl in the4-position, R₄ is hydrogen, n is 1 or 3 and s is 2 or 3.

Most preferred compounds of formula I are:

[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid;

racemic[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-2-propylphenoxy]aceticacid;

4-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]butanoicacid;

4-[4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoicacid;

[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid;

[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid;

[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]aceticacid;

4-[4-acetyl-3-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-2-propylphenoxy]butanoicacid; and

[4-acetyl-3-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]aceticacid.

Exemplary of other compounds of formula I are:

[4-acetyl-3-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]-aceticacid;

[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]aceticacid;

[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid;

racemic-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]methylaceticacid;

[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]aceticacid;

[4-acetyl-3-[3-(4-acetyl-3-hydroxy-6-iodo-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid;

[4-acetyl-3-[3-(4,6-diacetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-methylphenoxy]aceticacid;

[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-methylphenoxy)propoxy]-2-methylphenoxy]acetic acid;

[4-acetyl-3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid;

[4-acetyl-3-[3-(4-acetyl-2,6-dipropyl-3-hydroxyphenoxy)propoxy]-2-propylphenoxy]acetic acid;

[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-methylphenoxy)propoxy]-2-propylphenoxy]aceticacid;

4-[4-acetyl-3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]2-propylphenoxy]butanoicacid;

4-[4-acetyl-3-[3-(4,6-diacetyl-3-hydroxy-2-propylphenoxy)propoxy]2-propylphenoxy]butanoicacid;

4-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-2-propylphenoxy]butanoicacid.

3-[4-acetyl-3-[3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]propanoicacid;

5-[4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]pentanoicacid;

3-[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]propanoicacid;

5-[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]pentanoicacid;

3-[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]propanoicacid; and the like.

The compounds of formula I of the invention can be prepared ashereinafter described in Reaction Schemes I to IV which follow: ##STR7##wherein R, R₁, R₂, R₃, R₅ and n are as previously described, and Z"' islower alkylene or --(CH₂)_(s) [O(CH₂)_(s) ]_(t), wherein s is theinteger 2, 3 or 4, t is the integer 1, 2 or 3, R₄ ' is lower alkyl, R₄ "is hydrogen, and A is halogen or methylsulfonyloxy.

In Reaction Scheme I, the reaction of a compound of formula II(a) with acompound of formula III(a) to yield a compound of formula I(c) iscarried out under anhydrous conditions in an inert solvent, for example,acetone, methylethyl ketone, diethyl ketone, dimethylformamide or thelike, at the reflux temperature of the reaction mixture, indimethylformamide, preferably at a temperature in the range of 70°-100°C., and in the presence of an acid acceptor, for example, potassiumcarbonate or the like. The preferred solvent is a mixture of acetone anddimethylformamide. In a compound of formula III(a), A preferably isbromine and the reaction is sometimes carried out in the presence of acatalyst, for example, potassium iodide or the like. The resultingcompound of formula I(c) can be recovered utilizing conventionalmethods, for example, crystallization, chromatography or the like.

A resulting compound of formula I(c) can be converted to a compound offormula I(d) by hydrolysis which is carried out with an alkali metalhydroxide, for example, sodium hydroxide, potassium hydroxide or thelike, in a mixture of water and a water miscible alcohol, for example,methanol, ethanol or the like, at a temperature in the range of fromabout room temperature to the reflux temperature. The resulting compoundof formula I(d) can be recovered utilizing conventional methods, forexample, crystallization, chromatography or the like. ##STR8## whereinR, R₁, R₂, R₃, R₅ and n are as previously described, R₄ ' is lower alkyland R₄ " is hydrogen.

In Reaction Scheme II, the reaction of a compound of formula II(a) witha compound of formula III(b) to yield a compound of formula I(e) iscarried out at an elevated temperature, which usually is the refluxtemperature of the reaction mixture, in an inert solvent, for example,dimethylformamide, dioxane or the like, and in the presence of asuitable catalyst, for example, benzyltrimethylammonium hydroxide or thelike. Suitably, the reaction can be carried out by refluxing with t-amylalcohol in the presence of sodium t-amyloxide. The resulting compound offormula I(e) can be recovered utilizing conventional methods, forexample, crystallization, chromatography or the like.

A resulting compound of formula I(e) can be converted to a compound offormula I(f) by hydrolysis as described in Reaction Scheme I for theconversion of a compound of formula I(c) to a compound of formula I(d).The resulting compound of formula I(f) can be recovered utilizingconventional methods, for example, crystallization, chromatography orthe like. ##STR9## wherein A, R, R₁, R₂, R₃, R₅ and n are as previouslydescribed, Z"' is lower alkylene or --(CH₂)_(s) --[--O(CH₂)_(s) --]_(t)--, wherein s is the integer 2, 3 or 4, t is the integer 1, 2 or 3, R₄ 'is lower alkyl and R₄ " is hydrogen.

In Reaction Scheme III, the reaction of a compound of formula II(b) witha compound of formula III(c) to yield a compound of formula I(c) iscarried out utilizing the reaction conditions already described inReaction Scheme I for the reaction of a compound of formula II(a) and acompound of formula III(a). The resulting compound of formula I(c) canbe recovered utilizing conventional methods, for example,crystallization, chromatography or the like.

The conditions for the conversion of a compound of formula I(c) to acompound of formula I(d) by hydrolysis are described in Reaction SchemeI. The resulting compound of formula I(d) can be recovered utilizingconventional methods, for example, crystallization, chromatography orthe like. ##STR10## wherein R, R₁, R₂, R₃, R₅ and n are as previouslydescribed, R₄ ' is lower alkyl and R₄ " is hydrogen.

In Reaction Scheme IV, the reaction of a compound of formula II(c) witha compound of formula III(c) to yield a compound of formula I(e) iscarried out under the reaction conditions set out in Reaction Scheme IIfor the reaction of a compound of formula II(a) and a compound offormula III(b). The resulting compound of formula I(e) can be recoveredutilizing conventional methods, for example, crystallization,chromatography or the like.

The conversion of a compound of formula I(e) to a compound of formulaI(f) is carried out by hydrolysis as set out in Reaction Scheme II alsofor the conversion of a compound of formula I(e) to a compound offormula I(f). The resulting compound of formula I(f) can be recoveredutilizing conventional methods, for example, crystallization,chromatography or the like. ##STR11## wherein R₁, R₂, R₃, A and n are aspreviously described, and Z"' is lower alkylene or --(CH₂)_(s)[O(CH₂)_(s) ]_(t), wherein is the integer 2, 3 or 4, t is the integer 1,2 or 3, and R₄ ' is lower alkyl, and HAL is halogen.

In Reaction Scheme V, the reaction of a compound of formula IV with acompound of the formula ##STR12## to yield a compound of formula III(c)is carried out at the reflux temperature of the reaction mixture in aninert solvent, for example, acetone, methylethyl ketone, diethyl ketoneor the like, in the presence of an acid acceptor, for example, potassiumcarbonate, sodium carbonate or the like. This reaction can also becarried out utilizing a base, for example, sodium hydride or the like,under anhydrous conditions in a solvent, for example, dimethylformamide,tetrahydrofuran, dioxane or the like, at a temperature in the range offrom about 25° C. to about 70° C. The resulting compound of formulaIII(c) can be recovered utilizing conventional methods, for example,crystallization, chromatography or the like.

The conversion of a compound of formula III(c) to a compound of formulaIII(b) is conveniently carried out by reacting a compound of formulaIII(c) with epibromohydrin or epichlorohydrin in the presence ofpotassium carbonate, sodium carbonate or the like, in a solvent, forexample, acetone, methylethyl ketone, dimethylformamide or the like, ata temperature in the range of from about 55° C. to about 80° C., and inthe presence of a catalytic amount of potassium iodide or the like. Theresulting compound of formula III(b) can be recovered utilizingconventional methods, for example, crystallization, chromatography orthe like.

The conversion of a compound of formula III(c) to a compound of formulaIII(a) is conveniently carried out by reacting a compound of formulaIII(c) with a dihaloalkane, for example, a dibromoalkane such as1,3-dibromopropane, a dimesylate such as diethyleneglycol dimesylate ora dibromoether such as 1,11-dibromo-3,6,9-trioxaundecane in the presenceof potassium carbonate, sodium carbonate or the like, and in a solvent,for example, acetone, methylethyl ketone or mixtures of these withdimethylformamide or the like. The reaction is carried out at the refluxtemperature of the reaction mixture. The resulting compound of formulaIII(a) can be recovered utilizing conventional methods, for example,crystallization, chromatography or the like.

The starting materials of the formula ##STR13## wherein R₆ is hydroxy, A--Z"'--O-- or ##STR14## and A, Z"', R and R₅ are as previouslydescribed, are known compounds or can be prepared according to knownprocedures. Exemplary of such compounds are:

1-(2,4-dihydroxy-3-propylphenyl)ethanone;

1-(2,4-dihydroxy-3-methylphenyl)ethanone;

1-(2,4-dihydroxy-3-ethylphenyl)ethanone;

1-(2,4-dihydroxy-3,5-dipropylphenyl)ethanone;

1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone;

1-(5-acetyl-2,4-dihydroxy-3-propylphenyl)ethanone;

1-[4-(3-bromopropoxy)-2-hydroxy-3-propylphenyl]ethanone;

1-[4-(5-bromopentyloxy)-2-hydroxy-3-propylphenyl]ethanone;

1-[4-(3-bromopropoxy)-2-hydroxy-3-methylphenyl]ethanone;

1-[4-(3-bromopropoxy)-2-hydroxy-3-ethylphenyl]ethanone;

1-[4-(3-bromopropoxy)-3,5-dipropyl-2-hydroxyphenyl]ethanone;

1-[4-(3-bromopropoxy)-5-chloro-2-hydroxy-3-propylphenyl]ethanone;

1-[5-acetyl-4-(3-bromopropoxy)-2-hydroxy-3-propylphenyl]ethanone;

1-[2-hydroxy-4-(oxiranylmethoxy)-3-propylphenyl]ethanone;

1-[2-hydroxy-4-(oxiranylmethoxy)-3-methylphenyl]ethanone;

1-[2-hydroxy-5-iodo-4-(oxiranylmethoxy)-3-propylphenyl]ethanone;

1-[5-acetyl-2-hydroxy-4-(oxiranylmethoxy)-3-propylphenyl]ethanone;

1-[4-[2-(2-bromoethoxy)ethoxy]-2-hydroxy-3-propylphenyl]ethanone;

1-[4-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]-2-hydroxy-3-propylphenyl]ethanone;

1-[4-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]-2-hydroxy-3-propylphenyl]ethanone;

1-[4-[3-(3-bromopropoxy)propoxy]-2-hydroxy-3-propylphenyl]ethanone; andthe like.

The starting materials of the formula ##STR15## wherein R₆ is hydroxy, A--Z"'--O-- or ##STR16## and A, Z"', R₁, R₂, R₃, R₄ ' and n are aspreviously described,

can be prepared according to Reaction Scheme V. Exemplary of suchcompounds are:

4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester;

(4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid methyl ester;

[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid ethyl ester;

[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methyl ester;

[4-acetyl-3-(oxiranylmethoxy)-2-propylphenoxy]acetic acid ethyl ester;

[4-acetyl-3-(oxiranylmethoxy)-2-propylphenoxy]acetic acid methyl ester;

[6-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid ethyl ester;

[6-acetyl-3-(oxiranylmethoxy)-2-propylphenoxy]acetic acid ethyl ester;

[4-acetyl-3-(5-bromopentyloxy)-2-propylphenoxy]acetic acid ethyl ester;

(4-acetyl-3-hydroxyphenoxy)acetic acid ethyl ester;

[4-acetyl-3-(3-bromopropoxy)-phenoxy]acetic acid ethyl ester;

4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester;

4-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]butanoic acid ethylester;

racemic-(4-acetyl-3-hydroxy-2-propylphenoxy)-alpha-methylacetic acidethyl ester;

racemic-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]-alpha-methylacetic acid ethyl ester;

[4-acetyl-3-[2-(2-chloroethoxy)ethoxy]-2-propylphenoxy]acetic acid ethylester;

(4-acetyl-3-hydroxy-2-methylphenoxy)acetic acid methyl ester;

[4-acetyl-3-(3-bromopropoxy)-2-methylphenoxy]acetic acid methyl ester;

[4-acetyl-3-oxiranylmethoxy)-2-methylphenoxy]acetic acid methyl ester;

[4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester;

[4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester;

[4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]butanoic acidethyl ester;

and the like.

This invention also relates to the pharmaceutically acceptable salts ofthe phenoxycarboxylic acid derivatives of formula I, wherein R₄ ishydrogen. Said salts can be prepared by reacting an acid of formula Iwith a base having a non-toxic, pharmacologically and pharmaceuticallyacceptable cation. In general, any base which will form salt with acarboxylic acid and whose pharmacological properties will not cause anadverse physiological effect when ingested by a warmed blooded animal isconsidered as being within the scope of this invention. Suitable basesthus include, for example, the alkali metal and alkaline earth metalhydroxides, carbonates, for example, sodium hydroxide, potassiumhydroxide, calcium hydroxide, potassium carbonate and the like, ammonia,primary, secondary and tertiary amines, such as monoalkylamines,dialkylamines, trialkylamines, nitrogen containing heterocyclic amines,for example, piperidine, amino acids such as lysine, and the like. Thepharmaceutically acceptable salts thus produced are the functionalequivalent of the corresponding phenoxycarboxylic acids of formula I andone skilled in the art will appreciate that, to the extent that thesalts of the invention are useful in therapy, the variety of saltsencompassed by this invention are limited only by the criterion that thebases employed in forming the salts be both non-toxic andphysiologically acceptable.

The compounds of formula I of the invention are useful in the treatmentof disorders in which slow reacting substance of anaphylaxis (SRS-A) isa mediator. The compounds of formula I are therefore useful in thetreatment of allergic disorders which include skin afflictions, hayfever, chronic bronchitis, obstructive airways diseases such as asthma,allergic conditions of the eye, and allergic conditions of thegastro-intestinal tract, such as food allergies.

The useful antiallergic activity of the compounds of formula I isdemonstrated in vitro and in warm-blooded animals utilizing standardprocedures. Exemplary of such procedures are:

(a) Guinea Pig Ileum, In Vitro:

The guinea pig ileum bioassay system has been described by Orange andAusten, Adv. Immunol. 10: 105-144 (1969). A 1.5 cm segment is removedfrom animals weighing 300-400 g and suspended in an organ bathcontaining 10 ml of Tyrodes solution with 10⁻⁶ M atropine sulfate and10⁻⁶ M pyrilamine maleate. The bath is maintained at 37° C. and aeratedwith a mixture of 95% oxygen and 5% carbon dioxide. The SRS-A utilizedin this screen is obtained by challenging chopped lung fragments fromactively sensitized guinea pigs with egg albumin, in vitro. Adose-response curve to SRS-A challenge is established for the ileum. Thedose of SRS-A which gives 50% of the maximal contraction (EC₅₀) is thenused for subsequent challenge. The drug concentration which inhibits, by50%, the SRS-A-induced constriction of the guinea pig ileum isdetermined. In this bioassay system the standard SRS-A antagonist,7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid, has an IC₅₀ of 3.5×10⁻⁸ M.

(b) Guinea Pig Bronchoconstriction, In Vivo:

Male guinea pigs (Hostley strain) weighing 300 to 450 grams areanesthetized with urethane (2 g/kg) intraperitoneally and a polyethylenecannula is inserted into the jugular vein for intravenous drugadministration. Tracheal pressure is recorded from a cannula inserted inthe trachea and connected to a Statham pressure transducer. Respirationis paralyzed with succinyl choline (1.2 mg/kg, i.v.) and the animals aremechanically respirated (Howard rodent respirator) at 40 breaths/minuteand 2.5 cc tidal volume. Two minutes thereafter, propanolol (0.1 mg/kg,i.v.) is administered. Five minutes later, the animals are pretreatedintravenously for 30 seconds (at 10 mg/kg) with test drug or controlvehicle. The animals are subsequently challenged with a maximallyconstrictory dose of leukotriene E₄ also administered intravenously. Thechange (cm H₂ O) between pre and peak ventilatory pressure readings isaveraged for three control animals and five drug treated animals. Thepercent inhibition is calculated from the following formula:(Control-Drug Treated/Control)×100. For determination of oral activity,spontaneously breathing animals are pretreated orally for 2 hours (at100 mg/kg) prior to challange with leukitriene E₄.7-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylicacid elicits a 98% inhibition at 10 mg/kg, i.v., but is orally inactivein this test.

(c) Guinea Pig Bronchoconstriction, In Vivo (Aerosol):

Male guinea pigs (Hartley strain) weighing 300 to 500 g are anesthetizedwith urethane (2 g/kg) intraperitoneally and a polyethylene cannula isinserted into the jugular vein for drug administration. Trachealpressure is recorded from a cannula inserted in the trachea andconnected to a Statham pressure transducer. After surgical preparationof the animals, a period of time is allowed for pulmonary functions tostabilize. The test compound is administered according to the followingprotocol. Propanolol (0.1 mg/kg) is administered intravenously while theanimals breathed spontaneously. Five minutes thereafter, the animals areexposed for a five minute period to a 1% (w/v) aerosol solution of testcompound (adjusted to an alkaline pH where necessary for drugsolubilization) or to distilled water of the appropriate pH (for controlpurposes). A Monaghan (Model 750) ultrasonic nebulizer is used toadminister all test compounds by inhalation. The nebulizer ultrasonicfrequency is adjusted to produce particles in the 1-8μ diameter range(average 3μ). Aqueous solutions are prepared fresh and introduced intothe chamber of the nebulizer. The output of the nebulizer is madeavailable to the animal by directing a bias flow of aerosol through a ytube connected to the tracheal cannula. At the end of the exposureperiod, the animals are paralyzed with succinylcholine (1.2 mg/kg, i.v.)and mechanically respirated (Harvard rodent respirator) at 40breaths/minute and 2.5 cc tidal volume. Animals are then challenged witha maximum constrictory dose of leukotriene E₄ delivered intravenously 30seconds after administration of the succinylcholine.

The change (cm H₂ O) between pre and peak ventilatory pressure readingsis averaged for the three control animals and five drug treated animals.The percent inhibition is calculated from the following formula:##EQU1## When various drug concentrations are tested, the percentinhibition at each concentration is plotted as log concentration(abscissa) versus percent inhibition (ordinate) and the IC₅₀ isdetermined from linear regression analysis.

In order to determine the duration of action (doa), the animals areprepared as described above, except that the time between aerosolexposure and challenge with LTE₄ is varied. All compounds areadministered at a concentration of 1%. Duration of action is calculatedfrom plots of time (abscissa) versus % inhibition (ordinate). Theduration of action is defined as the time for the % inhibition to fallbelow 40%.

When the compounds of formula I, listed hereinafter in Table I, wereutilized in the test procedures described above, the result set out inTable I were obtained:

                                      TABLE I                                     __________________________________________________________________________                     Guinea Pig                                                                          Guinea Pig    Guinea Pig                                                Ileum Bronchoconstriction,                                                                        Bronchoconstriction,                                      In Vitro                                                                            In Vivo % I   In Vivo    Aerosol                                        (M)           100   Aerosol    Duration of                   Test Compound    IC.sub.50                                                                           10 mg/kg I.V.                                                                         mg/kg P.O.                                                                          IC.sub.50 (%)                                                                            Action (min.)                                                                        LD.sub.50              __________________________________________________________________________    [4-Acetyl-3-[3-(4-acetyl-3-                                                                    2 × 10.sup.-6                                                                 95      52    0.07.sup.(a)                                                                             90     500 mg/kg p.o.         hydroxy-2-propylphenoxy)                                90 mg/kg i.p.         propoxy]-2-propyl-                                                            phenoxy]acetic acid                                                           [4-Acetyl-3-[3-(4-acetyl-                                                                      2 × 10.sup.-7                                                                 97      81    0.44.sup.(a)      770 mg/kg p.o.         3-hydroxy-2-propylphenoxy)                             650 mg/kg i.p.         propoxy]-2-propylphenoxy]                                                     butanoic acid                                                                 racemic[4-Acetyl-3-[3-                                                                         1 × 10.sup.-6                                                                 89      29    0.1.sup.(b)                                                                              72                            (4-acetyl-3-hydroxy-2-propyl-                                                 phenoxy)-2-hydroxypropoxy]-                                                   2-propylphenoxy]                                                              acetic acid                                                                   4-[4-acetyl-3-[3-[3-(4-acetyl                                                                  2 × 10.sup.-7                                                                 93      56    0.008      37                            3-hydroxy-2-propylphenoxy)                                                    propoxy]propoxy]-2-propylphenoxy]                                             butanoic acid                                                                 [4-acetyl-3-[2-[2-[2-[2-(4-acetyl-                                                             3 × 10.sup.-7                                                                 90            0.04       73                            3-hydroxy-2-propylphenoxy)ethoxy]                                             ethoxy]ethoxy]ethoxy]-2-                                                      propylphenoxy]acetic acid                                                     [4-acetyl-3-[2-[2-[ 2-(4-acetyl-3-                                                             1 × 10.sup.-6                                                                 85       4    0.04       42     650 mg/kg p.o.         hydroxy-2-propylphenoxy)ethoxy]                        120 mg/kg i.p.         ethoxy]ethoxy]-2-propylphenoxy]                                               acetic acid                                                                   [4-acetyl-3-[2-[2-(4-acetyl-3-                                                                 2 × 10.sup.-7                                                                 86      26    0.02       14     800 mg/kg p.o.         hydroxy-2-propylphenoxy)                               170 mg/kg i.p.         ethoxy]ethoxy]-2-                                                             propylphenoxy]acetic acid                                                     4-[4-acetyl-3-[[5-(4-acetyl-                                                                   1 × 10.sup.-6                                                                 92      84    0.01       46                            3-hydroxy-2-propylphenoxy)                                                    pentyl]oxy]-2-propylphenoxy]                                                  butanoic acid                                                                 [4-acetyl-3-[5-(4-acetyl-3-                                                                    1 × 10.sup.-7                                                                 91      51    0.02       55     900 mg/kg p.o.         hydroxy-2-propylphenoxy)                               140 mg/kg i.p.         pentyloxy]-2-propylphenoxy]                                                   acetic acid                                                                   __________________________________________________________________________     .sup.(a) IC.sub.50 was determined using % inhibition valves obtained 30       seconds after exposure to test drug.                                          .sup.(b) IC.sub.50 was determined using % inhibition valves obtained 15       minutes after exposure to test drug.                                     

A compound of formula I or a salt thereof when R₄ is hydrogen, or acomposition containing a therapeutically effective amount of a compoundof formula I or a salt thereof, when R₄ is hydrogen, can be administeredby methods well known in the art. Thus, a compound of formula I, or asalt thereof when R₄ is hydrogen, can be administered either singly orwith other pharmaceutical agents, for example, antihistamines, mediatorrelease inhibitors, methyl xanthines, B₂ agonists or anti-asthmaticsteroids such as prednisone and prednisolone, orally, parenterally,rectally or by inhalation, for example, in the form of an aerosol,micropulverized powder or nebulized solution. For oral administrationthey can be administered in the form of tablets, capsules, for example,in admixture with talc, starch, milk sugar or other inert ingredients,that is, pharmaceutically acceptable carriers, or in the form of aqueoussolutions, suspensions, elixirs or aqueous alcoholic solutions, forexample, in admixture with sugar or other sweetening agents, flavoringagents, colorants, thickeners and other conventional pharmaceuticalexcipients. For parenteral administration, they can be administered insolutions or suspension, for example, as an aqueous or peanut oilsolution or suspension using excipients and carriers conventional forthis mode of administration. For administration as aerosols, they can bedissolved in a suitable pharmaceutically acceptable solvent, forexample, ethyl alcohol or water or combinations of miscible solvents,and mixed with a pharmaceutically acceptable propellant. Such aerosolcompositions are packaged for use in a pressurized container fitted withan aerosol valve suitable for release of the pressurized composition.Preferably, the aerosol valve is a metered valve, that is one which onactivation releases a predetermined effective dose of the aerosolcomposition.

In the practice of the invention, the dose of a compound of formula I ora salt thereof when R₄ is hydrogen to be administered and the frequencyof administration will be dependent on the potency and duration ofactivity of the particular compound of formula I or salt to beadministered and on the route of administration, as well as the severityof the condition, age of the mammal to be treated and the like. Doses ofa compound of formula I or a salt thereof when R₄ is hydrogencontemplated for use in practicing the invention are in the range offrom about 25 to about 1000 mg per day, preferably about 25 to about 250mg either as a single dose or in divided doses.

The Examples which follow further illustrate the invention. Alltemperatures are in degrees centigrade, unless other wise stated.

EXAMPLE 1 Preparation of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acidethyl ester

A mixture of 3.88 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.4 mlof ethyl bromoacetate and 4.0 g of anhydrous potassium carbonate in 50ml of anhydrous acetone was stirred at reflux for 6 hours. The reactionmixture was filtered and the filtrate was concentrated in vacuo to anoil which was purified by chromatography on silica gel. Elution with 20%ethyl acetate-toluene gave 4.13 g, mp 51°-52°, (73% yield) of(4acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester.

EXAMPLE 2 Preparation of[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid ethyl ester

A mixture of 4.13 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acidethyl ester, 7.6 ml of 1,3-dibromopropane and 3.0 g of anhydrouspotassium carbonate in 100 ml of anhydrous acetone was stirred at refluxfor 73 hours. An additional 1.0 g of potassium carbonate was added andreflux was continued for 19 hours at which time 1.0 g of potassiumcarbonate was added. After 16 hours reflux, the reaction mixture wasfiltered and the filtrate was concentrated in vacuo. The crude productwas chromatographed on 200 g of silica gel and eluted with 15% ethylacetate-toluene to give 4.82 g of[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid ethyl ester.

EXAMPLE 3 Preparation of[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxyacetic acid ethyl ester

A mixture of 1.17 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.41 gof 4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy acetic acid ethyl ester,1.66 g of anhydrous potassium carbonate and 0.1 g of potassium iodide in15 ml of anhydrous acetone and 15 ml of anhydrous dimethylformamide wasstirred at reflux for 18 hours. The solvent was removed in vacuo, 50 mlof 0.1N hydrochloric acid was added to the residue and the product wasextracted with methylene chloride. The dried, over sodium sulfate,extract was concentrated in vacuo and the crude product was crystallizedfrom methanol to yield 2.1 g, mp 45°-46°, (68% yield) of[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid ethyl ester.

EXAMPLE 4 Preparation of[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxyacetic acid

A suspension of 1.94 g of[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid ethyl ester in 5 ml of ethanol and 20 ml of 1.0N sodium hydroxidewas refluxed for 1 hour. After cooling, ice water was added and themixture was acidified. The precipitate was extracted with methylenechloride. The dried, over magnesium sulfate, extract was concentrated invacuo to an oil. Crystallization from ether-hexane gave 1.29 g, mp124°-125°, (71% yield) of[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid.

EXAMPLE 5 Preparation of[4-acetyl-3-(oxiranylmethoxy)-2-propylphenoxy]acetic acid methyl ester

A mixture of 7.75 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acidmethyl ester, 7.5 ml of epibromohydrin, 4.8 g of potassium iodide and6.0 g of anhydrous potassium carbonate in 80 ml of anhydrous acetone and40 ml of anhydrous dimethylformamide was stirred at reflux for 50 hours.The reaction mixture was filtered and the filtrate was concentrated invacuo to an oil which was purified by high pressure liquidchromatography (HPLC) using 10% ethyl acetate-hexane to yield 6.16 g of[4-acetyl-3-(oxiranylmethoxy)-2-propylphenoxy]acetic acid methyl ester.

EXAMPLE 6 Preparation of racemic[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-2-propylphenoxy]aceticacid methyl ester

A solution of 5.00 g of[4-acetyl-3-(oxiranylmethoxy)-2-propylphenoxy]acetic acid methyl ester,2.70 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 2 drops of TritonB in 30 ml of anhydrous dimethylformamide was stirred at reflux for 6hours. The solvent was removed in vacuo to give an oil which waspurified by high pressure liquid chromatography using 50% ethylacetate-hexane to yield 2.38 g, mp 124°-126°, of racemic[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-2-propylphenoxy]aceticacid methyl ester.

EXAMPLE 7 Preparation of racemic[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-2-propylphenoxy]aceticacid 0.25 molar hydrate

A solution of 2.28 g of racemic[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-2-propylphenoxy]aceticacid in 50 ml of methanol and 22 ml of 1.0N sodium hydroxide was stirredat reflux for 90 minutes. The methanol was removed in vacuo by 6Nhydrochloric acid was added to the residue to adjust the pH to 2.0. Theresultant solid was filtered and recrystallized from ethylacetate-hexane to give 1.90 g, mp 131°-134°, of racemic[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-2-propylphenoxy]aceticacid 0.25 molar hydrate.

EXAMPLE 8 Preparation of[4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]acetic acid ethyl ester

A mixture of 6.0 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acidethyl ester, 29 ml of 1,5-dibromopentane and 2.2 g of anhydrouspotassium carbonate in 150 ml of anhydrous acetone was stirred atreflux. Additional portions (2.2 g) of potassium carbonate were added at5, 21, 29 and 38 hours. Reflux was maintained for a total of 69 hours.The reaction mixture was filtered and the filtrate was concentrated invacuo to a yellow oil which was purified by chromatography on 100 g ofsilica gel. Elution with 25% ethyl acetate-hexane gave 9.2 g (100%) of[4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]acetic acid ethyl esteras an oil.

EXAMPLE 9 Preparation of[4-acetyl-3-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]aceticacid ethyl ester

A mixture of 3.0 g of 1-[2,4-dihydroxy-3-propylphenyl)ethanone, 6.65 gof [4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]acetic acid ethylester and 4.3 g of anhydrous potassium carbonate in 100 ml of anhydrousacetone and 50 ml of anhydrous dimethylformamide was stirred at refluxfor 24 hours. The reaction mixture was concentrated in vacuo to a redoil which was purified by high pressure liquid chromatography using 25%ethyl acetate-hexane to yield 4.95 g (59%) of[4-acetyl-3-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]aceticacid ethyl ester as a yellow oil.

EXAMPLE 10 Preparation of[4-acetyl-3-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]aceticacid

A solution of 4.8 g of[4-acetyl-3-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]aceticacid ethyl ester in 100 ml of methanol and 44 ml of 1N sodium hydroxidewas stirred at reflux for 2 hours. The methanol was removed in vacuo andthe pH of the residue was adjusted to 2.0. The product was filtered andrecrystallized from ether-hexane to give 4.00 g (88%), mp 86°-89°, of[4-acetyl-3-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]aceticacid.

EXAMPLE 11 Preparation of (4-acetyl-3-hydroxyphenoxy)acetic acid methylester

A mixture of 10.0 g of 1-(2,4-dihydroxyphenyl)ethanone, 6.2 ml of methylbromoacetate, and 13.6 g of anhydrous potassium carbonate in 125 ml ofanhydrous acetone was stirred at reflux for 3 hours. The reactionmixture was filtered and the filtrate was concentrated in vacuo to asolid which was recrystallized from methylene chloride-ether to give9.45 g (64%), mp 101°-103°, of (4-acetyl-3-hydroxyphenoxy)acetic acidmethyl ester.

EXAMPLE 12 Preparation of [4-acetyl-3-(3-bromopropoxy)phenoxy]aceticacid methyl ester

A mixture of 9.3 g of (4-acetyl-3-hydroxyphenoxy)acetic acid methylester, 21 ml of 1,3-dibromopropane and 8.6 g of anhydrous potassiumcarbonate in 500 ml of anhydrous acetone was stirred at reflux for 23hours. An additional 21 ml of 1,3-dibromopropane and 8.6 g of potassiumcarbonate were added and reflux was continued for 22 hours. The reactionmixture was filtered and the filtrate was concentrated in vacuo to anoil which was purified by high pressure liquid chromatography using 10%ethyl acetate-toluene to yield 12.5 g (87%), mp 67°-70°, of[4-acetyl-3-(3-bromopropoxy)phenoxy]acetic acid methyl ester.

EXAMPLE 13 Preparation of[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]aceticacid methyl ester

A mixture of 3.88 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 6.90 gof [4-acetyl-3-(3-bromopropoxy)phenoxy]acetic acid methyl ester, 5.5 gof anhydrous potassium carbonate in 100 ml of anhydrous acetone and 50ml of anhydrous dimethylformamide was stirred at reflux for 20 hours.The solvent was removed in vacuo to a dark solid which waschromatographed on 100 g of silica gel. Elution with 30% ethylacetate-toluene followed by recrystallization from methylenechloride-ether gave 4.85 g (53%), mp 103°-106°, of[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]aceticacid methyl ester.

EXAMPLE 14 Preparation of[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]aceticacid

A solution of 4.74 g of[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]aceticacid methyl ester in 150 ml of methanol and 52 ml of 1N sodium hydroxidewas stirred at reflux for 75 minutes. The methanol was removed in vacuoand the pH of the residue was adjusted to 2.0 with 6N hydrochloric acid.The solid was filtered and dried to give 4.39 g (95%), mp 151°-155°, of[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]aceticacid.

EXAMPLE 15 Preparation of[6-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methyl ester

A mixture of 5.0 g of1-[4-(3-bromopropoxy)-2-hydroxy-3-propylphenyl]ethanone, 3.0 ml ofmethyl bromoacetate, and 3.3 g of anhydrous potassium carbonate in 75 mlof anhydrous acetone was stirred at reflux for 4 hours. An additional2.0 g of potassium carbonate was added and reflux was continued for 13hours. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo to an oil which was purified by high pressureliquid chromatography using 5% ethyl acetate-toluene to give 3.5 g (58%)of [6-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methyl esteras an oil.

EXAMPLE 16 Preparation of[6-acetyl-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid methyl ester

A mixture of 1.72 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 3.43 gof [6-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methylester, 2.44 g of anhydrous potassium carbonate in 50 ml of anhydrousacetone and 25 ml of anhydrous dimethylformamide was stirred at refluxfor 18 hours. The reaction mixture was concentrated in vacuo and theresidue was purified by high pressure liquid chromatography to give 1.45g (33%) of[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid methyl ester as an oil.

EXAMPLE 17 Preparation of[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid

A solution of 1.41 g of6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid methyl ester in 50 ml of methanol and 14 ml of 1N sodium hydroxidewas stirred at reflux for 22 hours. The methanol was removed in vacuoand the pH of the residue was adjusted to 2.0 with 6N hydrochloric acid.The gummy product was extracted with ether and the crude extract waspurified by chromatography on 60 g of silica gel. Elution with a solventmixture of toluene:ethyl acetate:acetic acid (65:25:10) gave, afterrecrystallization from methylene chloride-ether, 0.51 g (38%), mp151°-155°, of[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid.

EXAMPLE 18 Preparation of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoicacid ethyl ester

A mixture of 15.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 15.0 gof ethyl 4-bromobutyrate, 16.0 g of anhydrous potassium carbonate in 200ml of anhydrous dimethylformamide was stirred and heated at 75° C. for24 hours. The solvent was removed in vacuo and the residue was purifiedby high pressure liquid chromatography using 2.5% ethyl acetate-tolueneto yield 7.62 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acidethyl ester as an oil.

EXAMPLE 19 Preparation of4-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]butanoic acid ethyl ester

A mixture of 7.6 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoicacid ethyl ester, 25 ml 1,3-dibromopropane and 2.0 g of anhydrouspotassium carbonate in 200 ml of anhydrous acetone was stirred atreflux. Additional 2.0 g portions of potassium carbonate were added at3, 7, 21, 47 and 55 hours. After a total reflux time of 78 hours, thereaction mixture was filtered and the filtrate was concentrated in vacuoto yield 4-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]butanoic acidethyl ester as a slightly impure oil.

EXAMPLE 20 Preparation of4-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]butanoicacid ethyl ester

A mixture of 3.00 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 6.65 gof 4-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]butanoic acid ethylester and 4.30 g of anhydrous potassium carbonate in 100 ml of anhydrousacetone and 50 ml of anhydrous dimethylformamide was stirred at refluxfor 19 hours. The solvent was removed in vacuo to give a red oil whichwas purified by high pressure liquid chromatography to yield 6.42 g(76%) of4-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]butanoicacid ethyl ester as an oil.

EXAMPLE 21 Preparation of4-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]butanoicacid

A solution of 6.22 g of4-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]butanoicacid ethyl ester in 100 ml of methanol and 57 ml of 1N sodium hydroxidewas stirred at reflux for 2 hours. The solvent was removed in vacuo andthe pH of the residue was adjusted to 2.0 with 6N hydrochloric acid. Thesolid was filtered and dried to give 5.16 g (87%), mp 96°-99°,4-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]butanoicacid.

EXAMPLE 22 Preparation ofracemic-(4-acetyl-3-hydroxy-2-propylphenoxy)-alpha-methylacetic acidethyl ester

A mixture of 10.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 8.4 mlof ethyl 2-bromopropionate and 10.7 g of anhydrous potassium carbonatein 125 ml of anhydrous acetone was stirred at reflux for 42 hours. Thereaction mixture was filtered and the filtrate was concentrated to anoil which was purified by high pressure liquid chromatography using 2%ethyl acetate-toluene to yield 11.4 g (73%) ofracemic-(4-acetyl-3-hydroxy-2-propylphenoxy)-alpha-methylacetic acidethyl ester as an oil.

EXAMPLE 23 Preparation ofracemic-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]methylacetic acidethyl ester

A mixture of 6.4 g ofracemic-(4-acetyl-3-hydroxy-2-propylphenoxy)-alpha-methylacetic acidethyl ester, 22 ml of 1,3-dibromopropane and 4.5 g of anhydrouspotassium carbonate in 175 ml of anhydrous acetone was stirred at refluxfor 52 hours. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo to 9.0 g ofracemic-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]methylacetic acidas a yellow oil.

EXAMPLE 24 Preparation of racemic[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]methylaceticacid ethyl ester

A mixture of 3.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 6.4 g ofracemic[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]methylacetic acidethyl ester and 4.3 g of anhydrous potassium carbonate in 100 ml ofanhydrous acetone and 50 ml of anhydrous dimethylformamide was stirredat reflux for 20 hours. The reaction mixture was filtered and thefiltrate was concentrated in vacuo to a red oil which was purified byhigh pressure liquid chromatography using 25% ethyl acetate-hexane togive 5.6 g (69%) ofracemic-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]methylaceticacid ethyl ester as a yellow oil.

EXAMPLE 25 Preparation ofracemic-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]methylaceticacid

A mixture of 5.4 g ofracemic-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]methylaceticacid ethyl ester in 100 ml of methanol and 50 ml of 1N sodium hydroxidewas stirred at reflux for 2 hours. The methanol was removed in vacuo andthe pH of the residue was adjusted to 2.0 with 6N hydrochloric acid. Thegummy product was extracted with methylene chloride and the extract wasdried over magnesium sulfate and concentrated in vacuo to an oil. Thecrude acid was dissolved in 50 ml of methanol and 10 ml of 1.0N sodiumhydroxide was added. The methanol was removed in vacuo, 25 ml of waterwas added and the sodium salt (0.33 molar hydrate) ofracemic-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]methylaceticacid was filtered and dried to give 4.2 g (78%), mp 92°-95°. The sodiumsalt was converted with 1N hydrochloric acid to the acid, whichcrystallized on addition of hexane. Filtration gaveracemic-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]methylaceticacid, mp 123°-126°.

EXAMPLE 26 Preparation of[4-acetyl-3-[2-(2-chloroethoxy)ethoxy]-2-propylphenoxy]acetic acd ethylester

A mixture of 6.0 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acidethyl ester, 25 ml of bis(2-chloroethyl)ether and 2.2 g of anhydrouspotassium carbonate in 150 ml of anhydrous acetone was stirred atreflux. After 24 hours, 2 g of potassium iodide and 50 ml of anhydrousdimethylformamide were added and reflux was continued. After 50 hours,2.2 g of potassium carbonate and 2 g of potassium iodide were added andafter 77 hours, 2.0 g of potassium carbonate was added. After a totalreflux time of 108 hours, the reaction mixture was concentrated in vacuoand the residue was purified by high pressure liquid chromatographyusing 25% ethyl acetate-hexane to give 5.96 g (72% yield) of[4-acetyl-3-[2-(2-chloroethoxy)ethoxy]-2-propylphenoxy]acetic acid ethylester as an oil.

EXAMPLE 27 Preparation of[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester

A mixture of 2.94 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 5.85 gof [4-acetyl-3-[2-(2-chloroethoxy)ethoxy]-2-propylphenoxy]acetic acidethyl ester, 4.2 g of anhydrous potassium carbonate, and 2.25 g ofpotassium iodide in 100 ml of anhydrous acetone and 50 ml of anhydrousdimethylformamide was stirred at reflux. Additional 2.0 g portions ofpotassium carbonate were added after 19, 26 and 51 hours. Reflux wascontinued for a total of 8 days and then the reaction mixture wasconcentrated in vacuo. The crude product was purified by liquidchromatography using 35% ethyl acetate-hexane to give 5.8 g (70% yield)of[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester.

EXAMPLE 28 Preparation of[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]aceticacid

A solution of 5.65 g of[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester in 100 ml of methanol and 50 ml of 1N sodium hydroxidewas stirred at reflux for 2 hours. The reaction mixture was concentratedin vacuo to remove the methanol and the pH of the residue was adjustedto 2.0 with 6N hydrochloric acid. The product was filtered andrecrystallized from ether-hexane to give 4.3 g (80% yield), mp 96°-99°,of[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]aceticacid.

EXAMPLE 29 Preparation of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoicacid methyl ester

A mixture of 5.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 5.4 g ofmethyl 6-bromohexanoate and 5.4 g of anhydrous potassium carbonate in 50ml of anhydrous dimethylformamide was stirred and heated at 75° for 10hours. The solvent was removed in vacuo and the residue was purified bycolumn chromatography on 125 g of silica gel. Elution with 25% ethylacetate-hexane gave 7.5 g (90% yield) of6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester as anoil.

EXAMPLE 30 Preparation of6-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]hexanoic acid methylester

A mixture of 6.0 g of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoicacid methyl ester, 19 ml of 1,3-dibromopropane and 2.0 g of anhydrouspotassium carbonate in 175 ml of anhydrous acetone was stirred at refluxfor 52 hours. The reaction mixture was concentrated in vacuo to give 8.1g (98% yield) of 6-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]hexanoicacid methyl ester as an oil.

EXAMPLE 31 Preparation of6-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]hexanoicacid methyl ester

A mixture of 2.62 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 6.00 gof 6-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]hexanoic acid methylester and 3.70 g of anhydrous potassium carbonate in 100 ml of anhydrousacetone and 50 ml of anhydrous dimethylformamide was stirred at refluxfor 20 hours. The reaction mixture was concentrated in vacuo and theresidue was purified by liquid chromatography using 30% ethylacetate-hexane to give 5.10 g (68% yield) of6-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]hexanoicacid methyl ester as an oil.

EXAMPLE 32 Preparation of6-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]hexanoicacid

A solution of 4.95 g of6-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]hexanoicacid methyl ester and 45 ml of 1N sodium hydroxide in 100 ml of methanolwas stirred at reflux for 2 hours. Most of the methanol was removed invacuo and the pH of the residue was adjusted to 2.0. The resultantproduct was filtered and recrystallized from methylene chloride-hexaneto yield 4.30 g (89% yield), mp 105°-108°, of6-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]hexanoicacid.

EXAMPLE 33 Preparation of1-(5-bromo-2,4-dihydroxy-3-propylphenyl)ethanone

To a cold suspension (7°) of 5 g (0.026 mol) of1-(2,4-dihydroxy-3-propylphenyl)ethanone in 150 ml of chloroform wasadded 27 ml (0.027 mol) of 1M bromine in chloroform dropwise. Themixture was stirred at 5° for 45 minutes and solvent was removed invacuo. The residue was extracted with hot hexane and the hexane extractwas boiled down to 50 ml and allowed to crystallize. Filtration gave 5.2g, melting point 67° (74% yield) of1-(5-bromo-2,4-dihydroxy-3-propylphenyl)ethanone.

EXAMPLE 34 Preparation of[4-acetyl-3-[3-(4-acetyl-6-bromo-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid methyl ester

A mixture of 2 g (0.0073 mol) of1-(5-bromo-2,4-dihydroxy-3-propylphenyl)ethanone, 2.84 g (0.0073 mol) of[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methyl esterand 1.52 g (0.011 mol) of anhydrous potassium carbonate in 150 ml ofanhydrous acetone was stirred at reflux for 20 hours. An additional 1 gof potassium carbonate was added and reflux was continued for a total of35 hours. The hot reaction mixture was filtered and the filtrate wasconcentrated in vacuo to a oil which was dissolved in ethyl acetate andwashed with 1N sodium hydroxide and sodium chloride solution. The crudeproduct was purified by HPLC, eluting with 25% ethyl acetate in hexaneto yield 2.33 g (55% yield) of[4-acetyl-3-[3-(4-acetyl-6-bromo-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid methyl ester as a pale yellow oil.

EXAMPLE 35 Preparation of[4-acetyl-3-[3-(4-acetyl-6-bromo-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid

To a solution of 2.1 g (0.0037 mol) of[4-acetyl-3-[3-(4-6-bromo-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid methyl ester in 50 ml of methanol was added 50 ml (0.05 mol) of 1Nsodium hydroxide. The mixture was stirred at 25° for 16 hours andacidified to pH 4. The gummy precipitate was dissolved in ethyl acetateand washed with sodium chloride solution. The gummy solid obtained onconcentration of the ethyl acetate was purified by C₁₈ reverse phasecolumn chromatography, eluting with 60% to 75% of methanol in water toyield 1.0 g, melting point 129°-130° (48% yield) of[4-acetyl-3-[3-(4-acetyl-6-bromo-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid.

EXAMPLE 36 Preparation of1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone

To a solution of 5.0 g (0.026 mol) of1-(2,4-dihydroxy-3-propylphenyl)ethanone in 125 ml of chloroform wasadded 32.3 ml of (0.030 mol) 0.94M chlorine in chloroform dropwise at25°. The mixture was stirred at 25° for 2.5 hours. The solvent wasremoved in vacuo and the residue was extracted with hot hexane. Thehexane extract was boiled down to 100 ml and allowed to crystallize.Filtration gave 3.0 g, melting point 96°. (51% yield) of1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone.

EXAMPLE 37 Preparation of[4-acetyl-3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid methyl ester

A mixture of 2 g (0.0088 mol) of1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone, 3.39 g (0.0088 mol)of [4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methyl esterand 1.8 g (0.013 mol) of anhydrous potassium carbonate in 150 ml ofanhydrous acetone was stirred at reflux for 20 hours. An additional 1.0g of potassium carbonate was added and reflux was continued for a totalof 35 hours. The hot reaction mixture was filtered and filtrate wasconcentrated in vacuo to an oil which was dissolved in ethyl acetate andwashed with 1N sodium hydroxide and sodium chloride solution. The crudeoil obtained on concentration of the ethyl acetate solution was purifiedby HPLC, eluting with 30% ethyl acetate in hexane to yield 2.7 g (58%yield) of[4-acetyl-3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid methyl ester as a pale yellow oil.

EXAMPLE 38 Preparation of[4-acetyl-3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid

To a solution of 1.94 g (0.0036 mol) of[4-acetyl-3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid methyl ester in 60 ml of methanol was added 60 ml of 1N sodiumhydroxide (0.06 mol). The mixture was stirred at 25° for 20 hours. Mostof the methanol was removed in vacuo and the aqueous solution wasacidified to pH 4. The gummy precipitate was dissolved in ethyl acetateand washed with sodium chloride solution. The oil obtained onconcentration of the ethyl acetate extract was purified by C₁₈ reversephase column chromatography, eluting with 60-80% methanol in water toyield a pale yellow oil which solidified. Recrystallization fromcyclohexane-ether gave 790 mg, melting point 119°-121° (42% yield) of[4-acetyl-3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid.

EXAMPLE 39 Preparation of4-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid ethyl ester

A mixture of 4 g (0.013 mol) of4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 17 g(0.065 mol) of diethylene glycol dimesylate and 3.6 g (0.026 mol) ofanhydrous potassium carbonate in 80 ml of anhydrous acetone and 40 ml ofanhydrous dimethylformamide was stirred at reflux for 20 hours. Anadditional 1.8 g of potassium carbonate was added and reflux wascontinued for a total of 44 hours. The reaction mixture was filtered andconcentrated in vacuo to an orange oil which was treated with ethylacetate and sodium chloride solution. The yellow oil obtained onconcentration of the ethyl acetate was purified by HPLC, eluting with15% ethyl acetate/toluene to yield 4.1 g (67% yield) of4-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]-ethoxy]-2-propylphenoxy]butanoicacid ethyl ester as a yellow oil.

EXAMPLE 40 Preparation of[4-acetyl-3-[2-[2-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]2-propylphenoxy]aceticacid ethyl ester

A mixture of 0.512 g (0.00224 mol) of1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone, 1.000 g (0.00224 mol)of[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester and 0.620 g (0.00448 mol) of anhydrous potassiumcarbonate in 20 ml of anhydrous acetone and 10 ml of anhydrousdimethylformamide was stirred at reflux for 24 hours. The reactionmixture was filtered and concentrated in vacuo to an oil which wastreated with ethyl acetate and sodium chloride solution. The crude oilobtained on concentration of the ethyl acetate was purified by columnchromatography, eluting with 20-30% ethyl acetate-hexane to yield 0.400g (31% yield) of[4-acetyl-3-[2-[2-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]2-propylphenoxy]aceticacid ethyl ester as a pale yellow oil.

EXAMPLE 41 Preparation of[4-acetyl-3-[2-[2-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]aceticacid

To a solution of 0.400 g (0.00069 mol) of[4-acetyl-3-[2-[2-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester in 15 ml of methanol was added 15 ml of 1N sodiumhydroxide (0.015 mol). The mixture was stirred at 25° for 5 hours andthe methanol was removed in vacuo. The aqueous solution was acidified topH 4, the gummy precipitate was dissolved in ethyl acetate and washedwith sodium chloride solution. The oil obtained on concentration of theethyl acetate was crystallized from cyclohexane to give 0.32 g, meltingpoint 89°-91° (84% yield) of[4-acetyl-3-[2-[2-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]aceticacid.

EXAMPLE 42 Preparation of4-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]butanoicacid ethyl ester

A mixture of 1 g (0.0052 mol) of1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.45 g (0.0052 mol) of4-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]-ethoxy]-2-propylphenoxy]butanoicacid ethyl ester and 2.6 g (0.019 mol) of anhydrous potassium carbonatein 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamidewas stirred at reflux for 19 hours. The reaction mixture was filteredand the filtrate was concentrated in vacuo to an oil which was treatedwith ethyl acetate and sodium chloride solution. The organic phase waswashed with 1N sodium hydroxide solution and sodium chloride solution.The yellow oil obtained on concentration of the ethyl acetate waspurified by column chromatography, eluting with 5% ethyl acetate-tolueneto yield 0.526 g (18% yield) of4-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]butanoicacid ethyl ester as a pale yellow oil.

EXAMPLE 43 Preparation of4-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]butanoicacid

To a solution of 0.526 g (0.0009 mol) of4-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]butanoicacid ethyl ester in 23 ml of methanol was added 23 ml (0.023 mol) of 1Nsodium hydroxide. The mixture was stirred at 25° for 6 hours and themethanol was removed in vacuo. The aqueous solution was acidified to pH3, the precipitate was dissolved in ethyl acetate and washed with sodiumchloride solution. The oil obtained on concentration of the ethylacetate was purified by column chromatography, eluting with 50% ethylacetate-hexane and ethyl acetate to yield 0.4 g (80% yield) of4-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]butanoicacid as a pale yellow oil which solidified (melting point 52°-58°).

EXAMPLE 44 Preparation of [4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester

A mixture of 3.3 g (0.012 mole) of(4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, 18.0 g(0.059) of triethyleneglycol dimesylate and 3.3 g (0.024 mole) ofanhydrous potassium carbonate in 100 ml of anhydrous acetone and 45 mlof anhydrous dimethylformamide was stirred at reflux for 26 hours. Thereaction mixture was concentrated in vacuo to yield an oil which wasdissolved in 60% ethyl acetate-toluene and passed through a column of 60g of silica gel. The eluent was concentrated in vacuo and purified byHPLC using 35% ethyl acetate-toluene to give 3.06 g (53% yield) of[4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester as an oil.

EXAMPLE 45 Preparation of[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester

A mixture of 1.16 g (0.006 mole) of1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.93 g (0.006 mole) of[4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester and 1.65 g (0.012 mole) of anhydrous potassiumcarbonate in 50 ml of anhydrous acetone and 25 ml of anhydrousdimethylformamide was stirred at reflux for 21 hours. The solvents wereremoved in vacuo and the residue was purified by HPLC using 40% ethylacetate-hexane to give 2.45 g (70% yield) of[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester as an oil.

EXAMPLE 46 Preparation of[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid

A solution of 2.35 g (0.004 mole) of[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester in 50 ml of methanol and 20 ml (0.02 mole) of 1.0Nsodium hydroxide was stirred at reflux for 90 minutes. Most of thesolvent was removed in vacuo and the pH of the residue was adjusted to2.0 with 6N HCl. The gummy product was extracted with methylenechloride. The dried (magnesium sulfate) extract was concentrated invacuo and the residue was crystallized from methylene chloride-hexane togive 2.06 g (92% yield) of[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid, mp 74°-77°.

EXAMPLE 47 Preparation of6-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]-2-propylphenoxy]hexanoicacid methyl ester

A mixture of 4.0 g (0.012 mole) of6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester, 16.3 g(0.062 mole) of diethyleneglycol dimesylate and 3.4 g (0.024 mole) ofanhydrous potassium carbonate in 90 ml of anhydrous acetone and 40 ml ofanhydrous dimethylformamide was stirred at reflux for 22 hours. Thesolvents were removed in vacuo and the residue was treated with 100 mlof 50% ethyl acetate-hexane. Some of the residual starting dimesylatewas insoluble and was removed by filtration. The filtrate wasconcentrated in vacuo and the residual oil was purified by HPLC to give4.8 g (80% yield) of6-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]-2-propylphenoxy]hexanoicacid methyl ester as an oil.

EXAMPLE 48 Preparation of6-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]hexanoicacid methyl ester

A mixture of 1.14 g (0.0059 mole) of1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.87 g (0.0059 mole) of6-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]-2-propylphenoxy]hexanoicacid methyl ester and 1.62 g (0.012 mole) of anhydrous potassiumcarbonate in 50 ml of anhydrous acetone and 25 ml of anhydrousdimethylformamide was stirred at reflux for 17 hours. The solvents wereremoved in vacuo and the residue was purified by HPLC using 35% ethylacetate-hexane to yield 2.65 g (77% yield) of6-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]hexanoicacid methyl ester.

EXAMPLE 49 Preparation of6-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]hexanoicacid

A solution of 2.55 g (0.0044 mole) of6-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]hexanoicacid methyl ester in 50 ml of methanol and 22 ml (0.022 mole) of 1.0Nsodium hydroxide was stirred at reflux for 90 minutes. Most of thesolvent was removed in vacuo and the pH of the residue was adjusted to2.0 with 6N hydrochloric acid. The gummy product was extracted withethyl acetate and the dried (magnesium sulfate) extract was concentratedin vacuo to an oil which slowly crystallized. Trituration with hexaneand filtration gave 2.14 g which was purified by chromatography on 50 gof silica gel. Elution with 60% ethyl acetate-hexane gave the pureproduct which was triturated with hexane and filtered to yield 1.52 g(61% yield), melting point 55°-57°, of6-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]hexanoic acid.

EXAMPLE 50 Preparation of[4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester

A mixture of 2.8 g (0.01 mole) of(4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, 11.0 g(0.034 mole) of 1,11-dibromo-3,6,9-trioxaundecane and 2.8 g (0.02 mole)of anhydrous potassium carbonate in 60 ml of anhydrous acetone and 30 mlof anhydrous dimethylformamide was stirred at reflux for 16 hours. Anadditional 1.4 g of potassium carbonate was added and reflux wascontinued for 24 hours. The solvents were removed in vacuo and theresidue was chromatographed on 200 g of silica gel. Elution with 10%ethyl acetate-toluene gave 3.2 g (62% yield) of[4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester as an oil.

EXAMPLE 51 Preparation of[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester

A mixture of 2.55 g (0.005 mole) of[4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester, 0.97 g (0.005 mole) of1-(2,4-dihydroxy-3-propylphenyl)ethanone and 1.00 g (0.0062 mole) ofanhydrous potassium carbonate in 60 ml of anhydrous acetone was stirredat reflux for 15 hours. An additional 0.5 g of potassium carbonate wasadded and reflux was continued for 15 hours. The solvent was removed invacuo and the residue was chromatographed on 300 g of silica gel.Elution with 30% ethyl acetate-toluene gave 1.25 g (40% yield) of[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid ethyl ester as an oil.

EXAMPLE 52 Preparation of [4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid

A solution of 1.25 g (0.002 mole) of[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-ethoxy]-2-propylphenoxy]aceticacid ethyl ester in 30 ml of methanol and 10 ml (0.01 mole) of 1.0Nsodium hydroxide was stirred at reflux for 5 hours. Most of the solventwas removed in vacuo and the pH of the residue was adjusted to 2.0 with6N hydrochloric acid. The product was extracted with methyl acetate andthe dried (magnesium sulfate) extract was concentrated in vacuo to anoil which was purified by chromatography on 75 g of silica gel. Elutionwith toluene-ethyl acetate-acetic acid (65:25:10) gave 0.79 g (66%yield) of[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid as an oil.

EXAMPLE 53 Preparation of4-[4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]butanoic acid ethylester

A mixture of 3.5 g (0.011 mole) of4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 15.4 ml(0.11 mole) of 1,5-dibromopentane and 1.2 g (0.0087 mole) of anhydrouspotassium carbonate in 60 ml of anhydrous acetone was stirred at refluxfor 77 hours. During the reflux period additional 1.4 g portions ofpotassium carbonate were added at 4, 21, 28 and 45 hours. The solventwas removed in vacuo and the residue was purified by HPLC using 17%ethyl acetate-hexane to yield 4.35 g (84% yield) of4-[4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]butanoic acid ethylester as an oil.

EXAMPLE 54 Preparation of4-[4-acetyl-3-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-2-propylphenoxy]butanoicacid ethyl ester

A mixture of 0.96 g (0.005 mole) of1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.26 g (0.005 mole) of4-[4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]butanoic acid ethylester and 1.36 g (0.010 mole) of anhydrous potassium carbonate in 40 mlof anhydrous acetone and 20 ml of anhydrous dimethylformamide wasstirred at reflux for 17 hours. The solvents were removed in vacuo andthe residue was purified by HPLC using 25% ethyl acetate-hexane to yield2.36 g (84% yield) of4-[4-acetyl-3-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-2-propylphenoxy]butanoicacid ethyl ester as an oil.

EXAMPLE 55 Preparation of4-[4-acetyl-3-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-2-propylphenoxy]butanoicacid

A solution of 2.26 g (0.004 mole) of4-[4-acetyl-3-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-2-propylphenoxy]butanoicacid ethyl ester in 50 ml of methanol and 20 ml (0.02 mole) of 1.0Nsodium hydroxide was stirred at reflux for 3 hours. Most of the solventwas removed in vacuo and the pH of the residue was adjusted to 2.0 with6N hydrochloric acid. The product was extracted with methylene chlorideand the dried (magnesium sulfate) extract was concentrated in vacuo. Theresidue was crystallized from methylene chloride-hexane to yield 1.87 g(87% yield), melting point 61°-66°, of4-[4-acetyl-3-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-2-propylphenoxy]butanoicacid.

EXAMPLE 56 Preparation of[4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]acetic acidethyl ester

A mixture of 2.5 g (0.0089 mole) of(4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, 11.6 g(0.045 mole) of 3,3'-dibromodipropyl ether, 1.0 g (0.0072 mole) ofpotassium carbonate in 50 ml of anhydrous acetone and 25 ml of anhydrousdimethylformamide was stirred at reflux for 66 hours. Additional 1.0 gportions of potassium carbonate were added after 6, 18, 26 and 42 hours.The reaction mixture was filtered and the filtrate was concentrated invacuo to yield an oil which was chromatographed on 125 g of silica gel.Elution with 10% ethyl acetate-toluene gave 1.9 g (47% yield) of[4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]acetic acidethyl ester as an oil.

EXAMPLE 57 Preparation of[4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]aceticacid ethyl ester

A mixture of 1.89 g (0.004 mole) of[4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]acetic acidethyl ester, 0.80 g (0.004 mole) of1-(2,4-dihydroxy-3-propylphenyl)ethanone, and 1.14 g (0.0082 mole) ofpotassium carbonate in 40 ml of anhydrous acetone and 20 ml of anhydrousdimethylformamide was stirred at reflux for 20 hours. The solvents wereremoved in vacuo and the residue was purified by HPLC using 35% ethylacetate-hexane to give 1.69 g (72% yield) of[4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]aceticacid ethyl ester as an oil.

EXAMPLE 58 Preparation of[4-Acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]aceticacid

A solution of 1.65 g (0.0029 mole) of[4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]aceticacid ethyl ester in 50 ml of methanol and 14.4 ml (0.014 mole) of 1.0Nsodium hydroxide was stirred at reflux for 2 hours. Most of the solventwas removed in vacuo and the pH of the residue was adjusted to 2.0. Theproduct was extracted with methylene chloride and the dried (magnesiumsulfate) extract was concentrated in vacuo to an oil which wascrystallized from etherhexane to give 1.28 g (81% yield), melting point86°-90°, of[4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]aceticacid.

EXAMPLE 59 Preparation of4-[4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]butanoic acidethyl ester

A mixture of 2.5 g (0.008 mole) of4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 10.6 g(0.041 mole) of 3,3'-dibromodipropyl ether and 1.0 g (0.0072 mole) ofpotassium carbonate in 50 ml of anhydrous acetone and 25 ml of anhydrousdimethylformamide was stirred at reflux for 66 hours. Additional 1.0 gportions of potassium carbonate were added at 6, 18, 26 and 42 hours.The reaction mixture was filtered and the filtrate was concentrated invacuo to yield an oil which was chromatographed on 150 g of silica gel.Elution with 7% ethyl acetate-toluene gave 2.16 g (55% yield) of4-[4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]butanoic acidethyl ester as an oil.

EXAMPLE 60 Preparation of4-[4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoicacid ethyl ester

A mixture of 2.13 g (0.0044 mole) of4-[4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]butanoic acidethyl ester, 0.85 g (0.0044 mole) of1-(2,4-dihydroxy-3-propylphenyl)ethanone and 1.2 g (0.0087 mole) ofpotassium carbonate in 40 ml of anhydrous acetone and 20 ml of anhydrousdimethylformamide was stirred at reflux for 20 hours. The solvents wereremoved in vacuo and the residue was purified by HPLC using 35% ethylacetate-hexane to give 2.15 g (82% yield) of[4-acetyl-3-[3-[3-(4-acetyl-B3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoic acidethyl ester as an oil.

EXAMPLE 61 Preparation of4-[4-Acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoicacid

A solution of 2.06 g (0.0034 mole) of4-[4-acetyl-3-[3-[3(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoicacid ethyl ester in 50 ml of methanol and 17 ml (0.017 mole) of 1.0Nsodium hydroxide was stirred at reflux for 2 hours. Most of the solventwas removed and the pH of the residue was adjusted to 2.0. The productwas extracted with methylene chloride. The extract was washed withwater, dried (magnesium sulfate) and concentrated in vacuo to give 1.81g (92% yield) of4-[4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoicacid as an oil.

EXAMPLE 62 Preparation of[4-Acetyl-3-[4-(4-iodobutoxy)butoxy]-2-propylphenoxy]acetic acid ethylester

A mixture of 2.5 g (0.0089 mole) of(4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, 17.0(0.0446 mole) of 4,4'-diiododibutyl ether and 1.0 g (0.0072 mole) ofanhydrous potassium carbonate in 75 ml of anhydrous acetone was stirredat reflux for 65 hours. Additional 1.0 g portions of potassium carbonatewere added at 4, 20, 28 and 44 hours. The reaction mixture was filteredand the filtrate was concentrated in vacuo to a residue which waspurified by HPLC using 5% ethyl acetate-toluene to give 2.87 g (61%yield) of [4-acetyl-3-[4-(4-iodobutoxy)butoxy]-2-propylphenoxy]aceticacid ethyl ester as an oil.

EXAMPLE 63 Preparation of[4-Acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]aceticacid ethyl ester

A mixture of 1.00 g (0.0052 mole) of1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.78 g (0.0052 mole) of[4-acetyl-3-[4-(4-iodobutoxy)butoxy]-2-propylphenoxy]acetic acid ethylester and 1.44 g (0.010 mole) of anhydrous potassium carbonate in 75 mlof anhydrous acetone was stirred at reflux for 18 hours. The reactionmixture was filtered and the filtrate was concentrated in vacuo. Theresidue was purified by HPLC using 35% ethyl acetate-hexane to give 2.72g (87% yield) of[4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]aceticacid ethyl ester as an oil.

EXAMPLE 64 Preparation of[4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]aceticacid

A solution of 2.617 g (0.0044 mole) of[4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]aceticacid ethyl ester in 50 ml of methanol and 21.8 ml of 1.0N sodiumhydroxide was stirred at reflux for 2 hours. Most of the solvent wasremoved in vacuo and the pH of the residue was adjusted to 2.0. Theproduct was extracted with methylene chloride and the dried (magnesiumsulfate) extract was concentrated in vacuo. The residue was crystallizedfrom ether-hexane to give 2.05 g (82% yield) of[4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]aceticacid, melting point 68°-71°.

EXAMPLE 65 Preparation of[4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]aceticacid ethyl ester

A mixture of 1.10 g (0.0049 mole) of1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone, 2.08 g (0.0049 mole)of [4-acetyl-3-[(5-bromopentyl)oxy]-3-propylphenoxy]acetic acid ethylester and 1.33 g (0.0097 mole) of potassium carbonate in 40 ml ofanhydrous acetone and 20 ml of anhydrous dimethylformamide was stirredat reflux for 22 hours. The reaction mixture was concentrated in vacuoand the residue was purified by HPLC using 25% ethyl acetate-hexane togive 0.96 g (34% yield) of[4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.

EXAMPLE 66 Preparation of[4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]aceticacid

A solution of 0.94 g (0.0016 mole) of[4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]aceticacid ethyl ester in 50 ml of methanol and 8.2 ml (0.0082 mole) of 1.0Nsodium hydroxide was stirred at reflux for 2 hours. Most of the solventwas removed in vacuo and the pH of the residue was adjusted to 2.0. Theproduct was extracted with methylene chloride and the dried (magnesiumsulfate) extract was concentrated in vacuo. The residue was crystallizedfrom etherhexane to give 0.710 g (79% yield) of[4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]aceticacid, melting point 77°-80°.

EXAMPLE 67 Preparation of4-[4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]butanoicacid ethyl ester

A mixture of 0.990 g (0.0043 mole) of1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone, 1.980 g (0.0043 mole)of 4-[4-acetyl-3-[(5-bromopentyl)oxy]-3-propylphenoxy]butanoic acidethyl ester and 1.2 g (0.0087 mole) of anhydrous potassium carbonate in40 ml of anhydrous acetone and 20 ml of anhydrous dimethylformamide wasstirred at reflux for 22 hours. The reaction mixture was concentrated invacuo and the residue was purified by HPLC using 25% ethylacetate-hexane to give 1.008 g (38% yield) of4-[4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]butanoicacid ethyl ester as an oil.

EXAMPLE 68 Preparation of4-[4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]butanoicacid

A solution of 0.978 g (0.0016 mole) of 4-[4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]butanoicacid ethyl ester in 50 ml of methanol and 8.1 ml (0.0081 mole) of 1.0Nsodium hydroxide was stirred at reflux for 2 hours. Most of the solventwas removed in vacuo and the pH of the residue was adjusted to 2.0. Theproduct was extracted with methylene chloride and the dried (magnesiumsulfate) extract was concentrated in vacuo to give 0.850 g (91% ofyield) of4-[4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]butanoicacid as an oil.

EXAMPLE 69 Preparation of4-[4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid ethyl ester

A mixture of 4.0 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoicacid ethyl ester, 19.9 g of triethylene glycol dimesylate and 3.6 g ofanhydrous potassium carbonate in 80 ml of anhydrous acetone and 40 ml ofanhydrous dimethylformamide was stirred at reflux for 23 hours. Thereaction mixture was filtered and the filtrate was concentrated in vacuoto an oil which was purified by high pressure liquid chromatographyusing 30% ethyl acetate-toluene to give 3.0 g (45% yield) of4-[4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid ethyl ester as an oil.

EXAMPLE 70 Preparation of4-[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid ethyl ester

A mixuture of 1.100 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.939g of4-[4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid ethyl ester and 1.56 g of anhydrous potassium carbonate in 80 ml ofanhydrous acetone and 40 ml of anhydrous dimethylformamide was stirredat reflux for 20 hours. The reaction mixture was filtered and thefiltrate was concentrated in vacuo to a dark oil which was purified byhigh pressure liquid chromatography using 40% ethyl acetatehexane togive 2.413 g (69% yield) of4-[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid ethyl ester as an oil.

EXAMPLE 71 Preparation of4-[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid

A soluton of 2.313 g of4-[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid ethyl ester and 19 ml of 1.0N sodium hydroxide in 50 ml of methanolwas stirred at reflux for 2 hours. Most of the methanol was removed invacuo and the residue was acidified. The product was extracted withmethylene chloride and the dried (magnesium sulfate) extract wasconcentrated in vacuo to give 2.058 g (93% yield) of4-[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid as a viscous oil.

EXAMPLE 72 Preparation of4-[4-acetyl-3-[3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoicacid ethyl ester

A mixture of 0.850 g of1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone, 1.811 g of4-[4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]butanoic acidethyl ester and 1.0 g of anhydrous potassium carbonate in 65 ml ofanhydrous acetone was stirred at reflux for 4 days. Additional 1.0 gportions of potassium carbonate were added after 21 and 30 hours. Thereaction mixture was filtered and the filtrate was concentrated in vacuoto a brown oil. Purification by high pressure liquid chromatographyusing 20% ethyl acetate-hexane gave 0.516 g (22% yield) of4-[4-acetyl-3-[3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoicacid ethyl ester as a yellow oil.

EXAMPLE 73 Preparation of4-[4-acetyl-3-[3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoicacid

A solution of 0.506 g of4-[4-acetyl-3-[3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoicacid ethyl ester in 4.0 ml of 1.0N sodium hydroxide and 20 ml ofmethanol was stirred at reflux for 2 hours. The methanol was removed invacuo and the residue was acidified. The product was extracted withethyl acetate and the dried (magnesium sulfate) extract was concentratedin vacuo to give 0.461 g (95% yield) of4-[4-acetyl-3-[3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoicacid as an oil.

EXAMPLE 74 Preparation of4-[4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy[-2-propylphenoxy]butanoicacid ethyl ester

A mixture of 3.08 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoicacid ethyl ester, 16.0 of 1,11-dibromo-3,6,9-trioxaundecane and 2.8 g ofanhydrous potassium carbonate in 75 ml of anhydrous acetone was stirredat reflux for 5 days. During this period, 1.0 g portions of potassiumcarbonate were added after 18 hours and after 25 hours. The reactionmixture was filtered and the filtrate was concentrated in vacuo to anoil (20 g) which was chromatographed on 200 g of silica gel using 10%ethyl acetatetoluene to give 3.24 g (59% yield) of4-[4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid ethyl ester as an oil.

EXAMPLE 75 Preparation of4-[4-acetyl-3-[2-[2-[2[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid ethyl ester

A mixture of 0.9500 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.677g of4-[4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid ethyl ester and 1.0 g of anhydrous potassium carbonate in 40 ml ofanhydrous acetone was stirred at reflux for 17 hours. An additional 1.0g of potassium carbonate was added and reflux was continued for 25hours. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo to an oil which was chromatographed on 200 g ofsilica gel. Elution with 30% ethyl acetate-toluene gave 2.3 g (71%yield) of4-[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid ethyl ester as an oil.

EXAMPLE 76 Preparation of 4-[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid

A solution of 2.30 g of4-[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid ethyl ester in 17 ml of 1.0N sodium hydroxide and 50 ml of methanolwas stirred at reflux for 7 hours. The methanol was removed in vacuo andthe residue was acidified. The product was extracted with ether and thedried (magnesium sulfate) extract was concentrated in vacuo to an oil(2.40 g). Chromatography on 150 g of silica gel and elution with asolvent mixture of 5% acetic acid: 70% toluene: 25% ethyl acetate gave1.72 g (78% yield) of4-[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoicacid as a viscous oil.

EXAMPLE 77 Preparation of4-[4-acetyl-3-[4-(4-iodobutyoxy)butoxy]-2-propylphenoxy]butanoic acidethyl ester

A mixture of 3.08 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoicacid ethyl ester, 19.0 g of 4,4'-diiododibutyl ether and 2.0 g ofanhydrous potassium carbonate in 75 ml of anhydrous acetone was stirredat reflux for 6 days. Additional 1.0 g portions of potassium carbonatewere added during this period after 17, 39 and 46 hours. The reactionmixture was filtered and the filtrate was concentrated in vacuo to anoil. Chromatography on 200 g of silica gel and elution with 10% ethylacetate-toluene gave 3.00 g (53% yield) of4-[4-acetyl-3-[4-(4-iodobutoxy)butoxy]-2-propylphenoxy]butanoic acidethyl ester as an oil.

EXAMPLE 78 Preparation of4-[4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]butanoicacid ethyl ester

A mixture of 0.871 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.536g of 4-[4-acetyl-3-[4-(4-iodobutoxy)butoxy]-2-propylphenoxy]butanoicacid ethyl ester and 0.94 g of anhydrous potassium carbonate in 40 ml ofanhydrous acetone was stirred at reflux for 17 hours. An additional 1.0g of potassium carbonate was added and reflux was continued for 25hours. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo to an oil which was chromatographed on 200 g ofsilica gel. Elution with 20% ethyl acetate-toluene gave 2.71 g (96%yield) of4-[4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]butanoicacid ethyl ester as an oil.

EXAMPLE 79 Preparation of4-[4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]butanoicacid

A solution of 2.71 g of4-[4-acetyl-3-[4-[4-(4acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]butanoicacid ethyl ester in 20 ml of 1.0N sodium hydroxide and 90 ml of methanolwas stirred at reflux for 6.5 hours. The methanol was removed in vacuoand the residue was acidified. The product was extracted with ether andthe dried (magnesium sulfate) extract was concentrated in vacuo to anoil. Chromatography on 150 g of silica gel and elution with a solventmixture of 5% acetic acid: 70% toluene: 25% ethyl acetate gave 2.32 g(90% yield) of4-[4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]butanoicacid as an oil.

EXAMPLE 80

    ______________________________________                                        CAPSULE FORMULATION                                                                      mg/capsule                                                         Ingredients  25 mg    50 mg    100 mg 200 mg                                  ______________________________________                                        [4-acetyl-3-  25       50      100    200                                     [3-(1-acetyl-3-                                                               hydroxy-2-                                                                    propylphenoxy)                                                                propoxy]-2-                                                                   propylphenoxy]                                                                acetic acid                                                                   Lactose      375      155      200    140                                     Starch        30       30       35     40                                     Talc          20       15       15     20                                     Weight of    450 mg   250 mg   350 mg 400 mg                                  capsule                                                                       ______________________________________                                    

Procedure

Mill[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid, lactose and starch in a suitable mixer. Mill. Add talc and mixwell. Encapsulate on suitable equipment.

EXAMPLE 81

    ______________________________________                                        TABLET FORMULATION                                                            (Wet granulation)                                                                        mg/tablet                                                          Ingredients  25 mg    50 mg    100 mg 200 mg                                  ______________________________________                                        ]4-acetyl-3-  25       50      100    200                                     [3-(4-acetyl-3-                                                               hydroxy-2-                                                                    propylphenoxy)                                                                propoxy]-2-                                                                   propylphenoxy]                                                                acetic acid                                                                   Lactose      280      153      187    171                                     Modified Starch                                                                             55       25       35     45                                     Pregelatinized                                                                              35       20       25     30                                     Starch                                                                        Distilled    --       --       --     --                                      water q.s.                                                                    Magnesium     5        2        3      4                                      Stearate                                                                      Weight of    400 mg   250 mg   350 mg 450 mg                                  tablet                                                                        ______________________________________                                    

Procedure

Mix,[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxyacetic acid, lactose, modified starch an pregelatinized starch in asuitable mixer. Granulate with sufficient distilled water to properconsistency. Mill. Dry in a suitable oven. Mill and mix with magnesiumstearate for 3 minutes. Compress on a suitable press equipped withappropriate punches.

EXAMPLE 82

    ______________________________________                                        TABLET FORMULATION                                                            (Direct Compression)                                                                             mg/tablet                                                  Ingredients        25 mg                                                      ______________________________________                                        [4-acetyl-3-[3-(4-acetyl-3-                                                                      25                                                         hydroxy-2-propylphenoxy)                                                      propoxy]-2-propylphenoxy]                                                     acetic acid                                                                   Lactose            181                                                        Avicel             55                                                         Direct Compression Starch                                                                        35                                                         Magnesium Stearate 4                                                          Weight of tablet   300        mg                                              ______________________________________                                    

Procedure

Mix[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]aceticacid with an equal amount of lactose. Mix well. Mix with avicel anddirect compression starch, and the remaining amount of lactose. Mixwell. Add magnesium stearate and mix for 3 minutes. Compression on asuitable press equipped with appropriate punches.

We claim:
 1. A compound of the formula ##STR17## wherein R is hydrogenor lower alkyl R₁ is hydrogen or lower alkyl, R₂ is lower alkanoyl, R₃is hydrogen or methyl, R₄ is hydrogen or lower alkyl, R₅ is hydrogen,halogen, lower alkyl or lower alkanoyl, Z¹¹ is --(CH₂)_(s) --O(CH₂)_(s)]_(t), wherein s is the integer 2, 3 or 4, t is the integer 1, 2 or 3,and n is an integer from 1 to 7, or, when R₄ is hydrogen,a salt thereofwith a pharmaceutically acceptable base.
 2. A compound in accordancewith claim 1, wherein R₂ is in the 4-position.
 3. A compound inaccordance with claim 2, wherein R and R₁ are lower alkyl, R₃ and R₅ arehydrogen and n is 1 or
 3. 4. A compound in accordance with claim 3,wherein R and R₁ are propyl, R₂ is acetyl, and s is 2 or
 3. 5. Acompound in accordance with claim 4, wherein R₄ is hydrogen.
 6. Acompound in accordance with claim 1,[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]aceticacid.
 7. A compound in accordance with claim 1,[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid.
 8. A compound in accordance with claim 1,[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]aceticacid.
 9. A compound in accordance with claim 1,4-[4-Acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoicacid.
 10. A pharmaceutical composition comprising a compound of theformula ##STR18## wherein R is hydrogen or lower alkyl, R₁ is hydrogenor lower alkyl, R₂ is lower alkanoyl, R₃ is hydrogen or methyl, R₄ ishydrogen or lower alkyl, R₅ is hydrogen, halogen, lower alkyl or loweralkanoyl, Z¹¹ is --(CH₂)_(s) --O(CH₂)_(s) ]_(t), wherein s is theinteger 2, 3 or 4, t is the integer 1, 2 or 3, and n is an integer from1 to 7, or, when R₄ is hydrogen,a salt thereof with a pharmaceuticallyacceptable base, and an inert carrier material.
 11. A pharmaceuticalcomposition in accordance with claim 10, wherein the compound of formulaIb is4-[4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoicacid.
 12. A method of treating allergic conditions which comprisesadministering a therapeutically effective amount of a compound of theformula ##STR19## wherein R is hydrogen or lower alkyl, R₁ is hydrogenor lower alkyl, R₂ is lower alkanoyl, R₃ is hydrogen or methyl, R₄ ishydrogen or lower alkyl, R₅ is hydrogen, halogen, lower alkyl or loweralkanoyl, Z¹¹ is --(CH₂)_(s) --O(CH₂)_(s) ]_(t), wherein s is theinteger 2, 3 or 4, t is the integer 1, 2 or 3, and n is an integer from1 to 7, or, when R₄ is hydrogen,a salt thereof with a pharmaceuticallyacceptable base.
 13. A method in accordance with claim 12, wherein thecompound of formula Ib is4-[4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-propoxy]-2-propylphenoxy]butanoicacid.
 14. A compound of the formula ##STR20## wherein R₁ is hydrogen orlower alkyl, R₂ is lower alkanoyl, R₃ is hydrogen or methyl, R₄ ' islower alkyl and n is an integer from 1 to
 7. 15. A compound of theformula ##STR21## wherein n is an integer from 1 to 7, R₁ is hydrogen orlower alkyl, R₂ is lower alkanoyl, R₃ is hydrogen or methyl, R₄ ' islower alkyl, Z¹¹¹ is lower alkylene or --(CH₂)_(s) --O(CH₂)_(s) ]_(t),wherein s is the integer 2, 3 or 4, t is the integer 1, 2 or 3, and A ishalogen or methylsulfonyloxy.
 16. A compound, in accordance with claim14, [4-acetyl-3-(oxiranylmethoxy)-2-propylphenoxy]acetic acid methylester.
 17. A compound, in accordance with claim 15,[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid ethyl ester.18. A compound, in accordance with claim 15,[4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]acetic acid ethylester.
 19. A compound, in accordance with claim 15,4-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]-butanoic acid ethylester.
 20. A compound, in accordance with claim 15,[4-acetyl-3-[2-(2-(2-chloroethoxy)ethoxy]-2-propylphenoxy]acetic acidethyl ester.
 21. A compound, in accordance with claim 15,4-[4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]butanoic acid ethylester.
 22. A compound, in accordance with claim 15,[4-acetyl-3-[3-(3-(3-bromopropoxy)propoxy]-2-propylphenoxy]acetic acidethyl ester.
 23. A compound, in accordance with claim 15,4-[4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]butanoic acidethyl ester.